Astrocytes | CHI3L1/YKL-40 and the Control of CNS Inflammation

A biomarker that turned out to be a driver.

CHI3L1/YKL-40 has been used for two decades as a fluid biomarker of neuroinflammation. Our work established that it is not a passive readout but an active signaling molecule: astrocyte-derived CHI3L1 engages specific receptors to suppress hippocampal neurogenesis, amplify demyelination, and shape the inflammatory microenvironment. We are now mapping its receptor logic across Alzheimer’s disease, neuromyelitis optica, and multiple sclerosis, and testing whether blocking it restores cognitive function.

Key papers: Science Advances 2025 — CHI3L1/YKL-40 inhibits neurogenesis in Alzheimer’s models · J Clin Invest 2026 — astrocyte-intrinsic CHI3L1 amplifies demyelination in NMO · Science Advances 2023 — CHI3L1 impairs neurogenesis in autoimmune neuroinflammation · Alzheimer’s & Dementia 2022 — review

Microglia | KLF2, APOE, and AD Risk Variants in 3D Hybrid Models

Human microglia, in a brain, at scale.

Human microglia behave differently in a dish than they do in tissue — which has limited what cultured models can tell us about Alzheimer’s risk. We developed a next-generation 3D hybrid human–rodent system that places human microglia in a physiologically relevant environment, and we use it to dissect how KLF2, APOE isoforms, and other AD-linked variants govern microglial state, synaptic pruning, and inflammatory tone across the aging brain.

Key papers: Cell 2017 — ApoE2/E3/E4 differentially stimulate APP transcription and Aβ secretion · J Neurosci 2019 — differential ApoE signaling parallels AD risk · Methods Mol Biol 2023 — iPSC microglia–astrocyte–neuron tri-culture protocol · Alzheimer’s & Dementia 2024 — AAIC Immunity Conference highlights

Neurons | BIN1, Endosomal Traffic, and the Spread of Tau

The second-strongest genetic risk factor for Alzheimer’s, and what it actually does.

BIN1 is among the most significant late-onset Alzheimer’s risk loci, yet its cellular function has remained murky. We study how BIN1 coordinates endosomal trafficking, autophagosome closure, and secretory autophagy in human neurons — and how its disruption drives the unconventional secretion and propagation of pathological tau. This work is the mechanistic foundation for a therapeutic program now in development.

Key papers: Cell Reports 2025 — BIN1 coordinates autophagosome closure and release · Neural Regen Res 2025 — bridging autophagy and endolysosomal dysfunction · Methods Mol Biol 2023 — autophagic flux assays for iPSC-derived human neurons

Oligodendrocytes | UBE3A, Myelin, and Angelman Syndrome

Angelman syndrome is not only a synapse disease.

UBE3A loss has been studied almost exclusively through the lens of neuronal and synaptic dysfunction. We found that oligodendrocytes are also directly affected: UBE3A deficiency disrupts oligodendrocyte maturation and myelination, and engages downstream estrogen receptor-β and neuron-to-microglia signaling that reshapes circuit connectivity. Restoring oligodendroglial homeostasis is an underexplored therapeutic axis for Angelman syndrome — one we are actively pursuing with the patient community.

Key papers: Molecular Autism 2025 — UBE3A stabilization of β-catenin preserves synaptic proteins · Preprint 2026 — targeting UBE3A and estrogen receptor-β signaling in oligodendroglia · Preprint 2026 — neuronal UBE3A loss engages a TNF-driven neuron-to-microglia axis · Int J Mol Sci 2025 — review